Tags

Type your tag names separated by a space and hit enter

Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis.
mBio. 2018 10 09; 9(5)MBIO

Abstract

Acute respiratory distress syndrome (ARDS) is immune-driven pathologies that are observed in severe cases of severe acute respiratory syndrome coronavirus (SARS-CoV) infection. SARS-CoV emerged in 2002 to 2003 and led to a global outbreak of SARS. As with the outcome of human infection, intranasal infection of C57BL/6J mice with mouse-adapted SARS-CoV results in high-titer virus replication within the lung, induction of inflammatory cytokines and chemokines, and immune cell infiltration within the lung. Using this model, we investigated the role of the complement system during SARS-CoV infection. We observed activation of the complement cascade in the lung as early as day 1 following SARS-CoV infection. To test whether this activation contributed to protective or pathologic outcomes, we utilized mice deficient in C3 (C3-/-), the central component of the complement system. Relative to C57BL/6J control mice, SARS-CoV-infected C3 -/- mice exhibited significantly less weight loss and less respiratory dysfunction despite equivalent viral loads in the lung. Significantly fewer neutrophils and inflammatory monocytes were present in the lungs of C3 -/- mice than in C56BL/6J controls, and subsequent studies revealed reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera of C3 -/- mice than in controls. These studies identify the complement system as an important host mediator of SARS-CoV-induced disease and suggest that complement activation regulates a systemic proinflammatory response to SARS-CoV infection. Furthermore, these data suggest that SARS-CoV-mediated disease is largely immune driven and that inhibiting complement signaling after SARS-CoV infection might function as an effective immune therapeutic.IMPORTANCE The complement system is a critical part of host defense to many bacterial, viral, and fungal infections. It works alongside pattern recognition receptors to stimulate host defense systems in advance of activation of the adaptive immune response. In this study, we directly test the role of complement in SARS-CoV pathogenesis using a mouse model and show that respiratory disease is significantly reduced in the absence of complement even though viral load is unchanged. Complement-deficient mice have reduced neutrophilia in their lungs and reduced systemic inflammation, consistent with the observation that SARS-CoV pathogenesis is an immune-driven disease. These data suggest that inhibition of complement signaling might be an effective treatment option following coronavirus infection.

Authors+Show Affiliations

Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA rbaric@email.unc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30301856

Citation

Gralinski, Lisa E., et al. "Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis." MBio, vol. 9, no. 5, 2018.
Gralinski LE, Sheahan TP, Morrison TE, et al. Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. mBio. 2018;9(5).
Gralinski, L. E., Sheahan, T. P., Morrison, T. E., Menachery, V. D., Jensen, K., Leist, S. R., Whitmore, A., Heise, M. T., & Baric, R. S. (2018). Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. MBio, 9(5). https://doi.org/10.1128/mBio.01753-18
Gralinski LE, et al. Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. mBio. 2018 10 9;9(5) PubMed PMID: 30301856.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. AU - Gralinski,Lisa E, AU - Sheahan,Timothy P, AU - Morrison,Thomas E, AU - Menachery,Vineet D, AU - Jensen,Kara, AU - Leist,Sarah R, AU - Whitmore,Alan, AU - Heise,Mark T, AU - Baric,Ralph S, Y1 - 2018/10/09/ PY - 2018/10/11/entrez PY - 2018/10/12/pubmed PY - 2019/3/22/medline KW - SARS-CoV KW - animal models KW - complement KW - coronavirus KW - respiratory viruses JF - mBio JO - mBio VL - 9 IS - 5 N2 - Acute respiratory distress syndrome (ARDS) is immune-driven pathologies that are observed in severe cases of severe acute respiratory syndrome coronavirus (SARS-CoV) infection. SARS-CoV emerged in 2002 to 2003 and led to a global outbreak of SARS. As with the outcome of human infection, intranasal infection of C57BL/6J mice with mouse-adapted SARS-CoV results in high-titer virus replication within the lung, induction of inflammatory cytokines and chemokines, and immune cell infiltration within the lung. Using this model, we investigated the role of the complement system during SARS-CoV infection. We observed activation of the complement cascade in the lung as early as day 1 following SARS-CoV infection. To test whether this activation contributed to protective or pathologic outcomes, we utilized mice deficient in C3 (C3-/-), the central component of the complement system. Relative to C57BL/6J control mice, SARS-CoV-infected C3 -/- mice exhibited significantly less weight loss and less respiratory dysfunction despite equivalent viral loads in the lung. Significantly fewer neutrophils and inflammatory monocytes were present in the lungs of C3 -/- mice than in C56BL/6J controls, and subsequent studies revealed reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera of C3 -/- mice than in controls. These studies identify the complement system as an important host mediator of SARS-CoV-induced disease and suggest that complement activation regulates a systemic proinflammatory response to SARS-CoV infection. Furthermore, these data suggest that SARS-CoV-mediated disease is largely immune driven and that inhibiting complement signaling after SARS-CoV infection might function as an effective immune therapeutic.IMPORTANCE The complement system is a critical part of host defense to many bacterial, viral, and fungal infections. It works alongside pattern recognition receptors to stimulate host defense systems in advance of activation of the adaptive immune response. In this study, we directly test the role of complement in SARS-CoV pathogenesis using a mouse model and show that respiratory disease is significantly reduced in the absence of complement even though viral load is unchanged. Complement-deficient mice have reduced neutrophilia in their lungs and reduced systemic inflammation, consistent with the observation that SARS-CoV pathogenesis is an immune-driven disease. These data suggest that inhibition of complement signaling might be an effective treatment option following coronavirus infection. SN - 2150-7511 UR - https://www.unboundmedicine.com/medline/citation/30301856/Complement_Activation_Contributes_to_Severe_Acute_Respiratory_Syndrome_Coronavirus_Pathogenesis_ L2 - http://mbio.asm.org/cgi/pmidlookup?view=long&pmid=30301856 DB - PRIME DP - Unbound Medicine ER -